It is known in these days that a large number of hormones and neurotransmitters function to increase or decrease the intracellular level of cyclic adenosine-3′,5′-monophosphate (cAMP) which is an intracellular second messenger, whereby regulating the cellular functions. The intracellular cAMP level is regulated by synthesizing and degradating enzymes. Thus, cAMP is produced by adenyl cyclases and degradated by phosphodiesterase (PDE). These degradating enzymes also regulate the degradation of cyclic guanosine-3′,5′-monophosphate.
Seven isozymes of the PDE have been found so far [Physiological Reviews, Vol.75, p725 (1995), Endocrine Reviews, Vol.16, p370, (1995)], and each functions, in various cells such as those in central nervous system, circulatory organs, respiratory organs, digestive organs, genital organs, blood cells and tracheal smooth muscles, to regulate intracellular cAMP and cGMP levels, whereby controlling the cellular functions. It is also known that in an inflammatory cell such as an eosinophile, neutrophile, monocyte, T-lymphocyte and macrophage a PDE isozyme referred to as PDE type-IV exists predominantly [Clinical and Experimental Allergy, Vol.22, p337 (1992)].
Pharmaceuticals, which can broadly be classified into three groups, are employed as therapeutic agents against a bronchial asthma. Thus, the three types including bronchodilators (for example, β-adrenaline receptor agonists), antiinflammatory agents (for example, corticosteroids) and xanthine derivatives having both of the bronchodilating effect and antiinflammatory effect (for example, theophylline) are employed. Among these, theophylline has been employed as a therapeutic agent against asthma for a long time. Theophylline is becoming more interesting in these days since its bronchodilating effect has been found to be derived from a PDE-inhibiting effect. However, theophylline is a non-selective PDE inhibitor and sometimes exhibits a cardiovascular side effect. Then, its blood level should strictly be controlled to reduce the side effect. Accordingly, a medicament for treating an inflammatory disease such as asthma which inhibits the PDE type-VI selectively and which has no effects on other isozymes of the PDE is desired.
A study indicating a possibility that a PDE type-IV-selective inhibitor is an effective therapeutic agent against an inflammatory disease such as asthma was reported [Pulmonary Pharmacology, Vol.7, p1 (1994)]. Thus, it was suggested that a PDE type-IV-selective inhibitor has the both of an antiinflammatory effect and a bronchodilating effect and may exhibit a therapeutic effect on an inflammatory disease such as asthma. In fact, compounds having inhibitory effects selectively on the PDE type-IV are subjected currently to an extensive development all over the world. For example, rolipram (JP-A-50-157360) having the structure represented by Formula: and SB 207499 [The Journal of Pharmacology and Experimental Therapeutics, Vol.287, p988 (1998), Journal of Medicinal Chemistry, Vol.41, p821 (1998)] represented by Formula: are under development. However, any of those listed above has not been employed clinically, and a further useful agent is desired to be developed.
On the other hand, a method for synthesizing a compound represented by Formula: is disclosed in Indian Journal of Chemistry, Section B, Vol.31B, p578 (1992).
Moreover, an antibacterial compound represented by Formula: is also disclosed in Indian Journal of Chemistry, Section B, Vol.33B, p552 (1994).
A potent selective PDE type-IV inhibitor having a novel chemical structure is expected to have a sufficient prophylactic or therapeutic effect in a wide range of diseases accompanied with inflammations, and is desired to be developed. The objective of the invention is to provide novel heterocyclic compounds which have selective PDE type-IV-inhibiting effect and increase the intracellular cAMP level whereby exhibiting bronchodilating and antiinflammatory effects and which is also excellent in terms of the safety.